Gender differences in the association of blood and urine cadmium concentrations with peripheral arterial disease (PAD) were evaluated by using data from 6,456 US adults aged ≥40 years who participated in the 1999-2004 National Health and Nutrition Examination Survey. PAD was defined as an ankle-brachial blood pressure index of <0.9 in at least one leg. For men, the adjusted odds ratios for PAD comparing the highest with the lowest quintiles of blood and urine cadmium concentrations were 1.82 (95% confidence interval (CI): 0.82, 4.05) and 4.90 (95% CI: 1.55, 15.54), respectively, with a progressive dose-response relation and no difference by smoking status. For women, the corresponding odds ratios were 1.19 (95% CI: 0.66, 2.16) and 0.56 (95% CI: 0.18, 1.71), but there was evidence of effect modification by smoking: among women ever smokers, there was a positive, progressive dose-response relation; among women never smokers, there was a U-shaped dose-response relation. Higher blood and urine cadmium levels were associated with increased prevalence of PAD, but women never smokers showed a U-shaped relation with increased prevalence of PAD at very low cadmium levels. These findings add to the concern of increased cadmium exposure as a cardiovascular risk factor in the general population.